Quinolone carboxylic acids, derivatives thereof, and methods of making and using same

ABSTRACT

A process of preparing a quinolone carboxylic acid or its derivatives having Formula I, Ia, or IV, as shown herein, comprises using a starting quinolone that already has one or more desired substituents at one or more particular positions on the quinolone ring and preserving the orientation of such substituents throughout the synthesis. The present process comprises fewer steps than prior-art processes. The present process also can include a simple separation of a desired enantiomer of the quinolone carboxylic acid or its derivatives from the enantiomeric mixture. Pharmaceutical compositions comprising fluoroquinolones prepared by the present process can be used effectively against a variety of microbial pathogens.

BACKGROUND OF THE INVENTION

The present invention relates to quinolone carboxylic acids, derivativesthereof, and methods of making and using the same. In particular, thepresent invention relates to fluoroquinolone carboxylic acids,derivatives thereof, methods of making and using the same.

Bacterial pathogens continue to pose a serious threat to public healthas indicated by a worldwide resurgence of bacterial diseases. One aspectof this resurgence appears to be the result of prior widespread, andlargely effective, therapeutic and prophylactic use of antibiotics,which, unfortunately, over time has also selected for resistant strainsof various bacterial pathogens. Of particular concern to the publichealth has been the emergence and proliferation of bacterial strainsthat are resistant to multiple antibiotics in the current arsenal ofantimicrobial agents. Such multiantibiotic-resistant (“MAR”) bacterialstrains include species of Gram-positive bacteria, such as,antibiotic-resistant strains of Staphylococcus aureus, Enterococcusfecalis, and Enterococcus fectum, which, along with antibiotic-resistantGram-negative strains of Escherichia coil, constitute the most frequentetiological agents of nosocomial (hospital-acquired) diseases, such assepticemia, endocarditis, and infections of wounds and the urinarytract. S. aureus is currently the most frequent cause of nosocomialbacteremia and skin or wound infection. Streptococcus pneumoniae causesseveral serious and life-threatening diseases, including a contagiousmeningitis, bacteremia, and otitis media. Annual mortality from S.pneumoniae infection alone is estimated at between 3-5 million personsglobally. More recently, clinical accounts of highly aggressive skin andtissue infections by “flesh-eating” strains of Group-A streptococcusbacteria, such as Streptococcus pyogenes, has heightened the concern andneed for new or improved antibacterial agents.

Quinolones constitute a group of antibiotics that have been availablesince the early 1960s and have proved to be valuable antibacterialagents. Quinolone carboxylic acid derivatives having various chemicalstructures have been synthesized, developed, and marketed. Nalidixicacid (1,4-dihydro-1-ethyl-7-methyl-1,8-naphthyridin-4-one-3-carboxylicacid), the progenitor of the series, was used primarily as aurinary-tract antiseptic. Later development provided agents with broaderactivity, increased potency against selected pathogens and improvedpharmacokinetic and pharmacodynamic properties.

From a medical utility viewpoint, the quinolones are classified asfirst-, second-, and third-generation compounds. First-generationcompounds like piromidic acid(8-ethyl-5,8-dihydro-5-oxo-2-(1-pyrrolidinyl)pyrido(2,3-d)pyrimidine-6-carboxylicacid) and pipemidic acid(8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)pyrido(2,3-d)pyrimidine-6-carboxylicacid) provided coverage for Gram-negative Enterobacteriaceae. Thesecond-generation compounds are divided into those with enhanced butpredominant Gram-negative activity, against pathogens like Escherichiacoli and Pseudomonas aeruginosa, and those with balanced broad-spectrumactivity (norfloxacin, pefloxacin, enoxacin, fleroxacin, lomefloxacin,ciprofloxacin, ofloxacin, rufloxacin, nadifloxacin). Norfloxacin,ofloxacin, and ciprofloxacin have, therefore, been used mainly fortreatment of diseases including urinary tract infections,gastrointestinal infections, sexually transmitted diseases and the like.Third-generation antibiotics (levofloxacin, pazufloxacin, sparfloxacin,clinafloxacin, sitafloxacin, trovafloxacin, tosufloxacin, temafloxacin,grepafloxacin, balofloxacin, moxifloxacin, gatifloxacin) are those withenhanced activity against Gram-positive cocci (notably clinafloxacin,sitafloxacin, trovafloxacin for Streptococcus pneumoniae) and, foressentially all the third-generation quinolones, activity also againstGram-negative Haemophilus influenzae and Legionella pneumophila, andagainst anaerobes and atypical pathogens. Levofloxacin, moxifloxacin,and gatifloxacin have, therefore, found use for community-acquiredinfections such as those of the upper and lower respirator) tractinfections (“RTI”) like pneumonia, sinusitis and pharyngitis, and forskin and soft tissue infections (“SSI”) caused by Gram-positive strainsof staphylococci, pneumococci, streptococci, and enterococci.

The improvements seen in most of the third-generation antibiotics incurrent use are generally attributed to their uniqueness in inhibitingDNA gyrase and topoisomerase IV of the bacterial targets. Threecategories of quinolone inhibition have been suggested. Type Iquinolones (norfloxacin, enoxacin, fleroxacin, ciprofloxacin,lomefloxacin, trovafloxacin, grepafloxacin, ofloxacin and levofloxacin)indicate a preference for topoisomerase IV inhibition. Type IIquinolones (nadifloxacin and sparfloxacin) indicate a preference for DNAgyrase inhibition. Type III quinolones to which some of thethird-generation quinolones belong (e.g., gatifloxacin, pazufloxacin,moxifloxacin and clinafloxacin) display, however, a dual-targetingproperty, and equally influence DNA gyrase inhibition and topoisomeraseIV inhibition. (M. Takei, et al. Antimicrobial Agents and Chemotherapy,Vol. 45, 3544-49 (2000)). DNA gyrase is the primary target in bacteria,and thus is explained the weaker activity in Gram-positive bacteria ofthe topoisomerase IV-targeting second-generation quinolones likenorfloxacin, ciprofloxacin, ofloxacin, and levofloxacin. The unusualactivity of nadifloxacin described in the literature, especially againstGram-positive S. aureus, now can be explained by its ability to targetDNA gyrase (N. Oizumi, et al., J. Infect. Chemother., Vol. 7, 191-194(2001)). That some third-generation quinolones are primarily capable oftargeting topoisomerase IV in Gram-positive staphylococci, and DNAgyrase in Gram-positive S. pneumoniae, explains the advantages providedby the dual-targeting third-generation quinolones like moxifloxacin andgatifloxacin. However, because of continuing threat of new strains ofantibiotic-resistant bacteria that may surface in the future, continuedeffort has been devoted to develop new broad-spectrum antibiotics.

A family of fluoroquinolones was recently developed, and some compoundsof this family show good antimicrobial activity against a wide range ofGram-positive and Gram-negative bacteria. See U.S. Pat. Nos. 5,385,900;5,447,926; 6,685,958; and 6,699,492; all of which are incorporatedherein by reference in their entirety. Because of the promise of theirtherapeutic value, it is very desirable, in one aspect to developimproved processes for preparing this family of fluoroquinolones inorder to allow for a more widespread availability of these compounds.

SUMMARY OF THE INVENTION

In general, the present invention provides an improved process forpreparing fluoroquinolones that have Formula I or salts thereof.

wherein R¹ is selected from the group consisting of hydrogen,unsubstituted lower alkyl groups, substituted, lower alkyl groups,cycloalkyl groups, unsubstituted C₅-C₂₄ aryl groups, substituted C₅-C₂₁aryl groups, unsubstituted C₅-C₂₄ heteroaryl groups, substituted C₅-C₂₄heteroaryl groups, and groups that can be hydrolyzed in living bodies;R² is selected from the group consisting of hydrogen, unsubstitutedamino group, and amino groups substituted with one or two lower alkylgroups; R³ is selected from the group consisting of hydrogen,unsubstituted lower alkyl groups, substituted lower alkyl groups,cycloalkyl groups, unsubstituted lower alkoxy groups, substituted loweralkoxy groups, unsubstituted C₅-C₂₄ aryl groups, substituted C₅-C₂₄ andgroups, unsubstituted C₅-C₂₄ heteroaryl groups, substituted C₅-C₂₄heteroaryl groups, unsubstituted C₅-C₂₄ aryloxy groups, substitutedC₅-C₂₄ aryloxy groups, unsubstituted C₃-C₂₄ heteroaryloxy groups,substituted C₅-C₂₄ heteroaryloxy groups, and groups that can behydrolyzed in living bodies; X is selected from the group consisting ofhalogen atoms; Y is selected from the group consisting of CH₂, O, S, SO,SO₂, and NR⁴, wherein R⁴ is selected from the group consisting ofhydrogen, unsubstituted lower alkyl groups, substituted lower alkylgroups, and cycloalkyl groups; and Z is selected from the groupconsisting of oxygen and two hydrogen atoms.

In one aspect, a process of preparing fluoroquinolones having Formula Icomprises contacting a first compound having Formula II with a secondcompound having Formula III to produce a fluoroquinolone having FormulaI, wherein the first compound and the second compound are represented by

wherein R¹, R², R³, X, Y, and Z have the meanings as disclosed above.

In another aspect, a process of preparing fluoroquinolones havingFormula IV comprises: (a) contacting a first compound having Formula IIwith a third compound having Formula V to produce a fourth compoundhaving Formula VI, wherein the fluoroquinolones having Formula IV, thefirst compound, the third compound, and the fourth compound arerepresented by

wherein R¹, R³, X, Y, and Z have the meanings as disclosed above and R⁵comprises a protected amino group having a formula of —NR⁶, wherein R⁶comprises a protecting group that is capable of leaving the protectedamino group —NR⁶, and (b) contacting the fourth compound with a catalystto effect a cleavage of the protecting group from the —NR⁶ group, toproduce a fluoroquinolone having Formula IV.

In a further aspect, the present invention provides a process forpreparing fluoroquinolones having Formula I. The process comprises: (a)contacting a compound having Formula XIII with a compound having FormulaIII to produce a compound having Formula XIV; and (b) halogenating thecompound having Formula XIV with a halogenating agent to produce thefluoroquinolones having Formula I; wherein R¹ is selected from the groupconsisting of hydrogen, unsubstituted lower alkyl groups, substitutedlower alkyl groups, cycloalkyl groups, unsubstituted C₅-C₂₄ aryl groups,substituted C₅-C₂₄ aryl groups, unsubstituted C₅-C₂₄ heteroaryl groups,substituted C₅-C₂₄ heteroaryl groups, and groups that can be hydrolyzedin living bodies; R² is selected from the group consisting of hydrogen,unsubstituted amino group, and amino groups substituted with one or twolower alkyl groups; R³ is selected from the group consisting ofhydrogen, unsubstituted lower alkyl groups, substituted lower alkylgroups, cycloalkyl groups, unsubstituted lower alkoxy groups,substituted lower alkoxy groups, unsubstituted C₅-C₂₄ aryl groups,substituted C₅-C₂₄ aryl groups, unsubstituted C₅-C₂₄ heteroaryl groups,substituted C₅-C₂₄ heteroaryl groups, unsubstituted C₅-C₂₄ aryloxygroups, substituted C₅-C₂₄ aryloxy groups, unsubstituted C₅-C₂₄heteroaryloxy groups, substituted C₅-C₂₄ heteroaryloxy groups, andgroups that can be hydrolyzed in living bodies; X is selected from thegroup consisting of halogen atoms; Y is selected from the groupconsisting of CH₂, O, S, SO, SO₂, and NR⁴, wherein R⁴ is selected fromthe group consisting of hydrogen, unsubstituted lower alkyl groups,substituted lower alkyl groups, and cycloalkyl groups; and Z is selectedfrom the group consisting of oxygen and two hydrogen atoms. Thecompounds having Formulae XIII, III, and XIV are shown below.

In a further aspect, the present invention provides quinolone carboxylicacids prepared by any process disclosed herein and their derivatives(such as their salts or esters), and methods of using such quinolonecarboxylic acids and derivatives.

Other features and advantages of the present invention will becomeapparent from the following detailed description and claims.

DETAILED DESCRIPTION

As used herein, the term “lower alkyl” or “lower alkyl group” means aC₁-C₁₅ linear- or branched-chain saturated aliphatic hydrocarbonmonovalent group, which may be unsubstituted or substituted. The groupmay be partially or completely substituted with halogen atoms (F, Cl,Br, or I). Non-limiting examples of lower alkyl groups include methyl,ethyl, n-propyl, 1-methylethyl(isopropyl), n-butyl, n-pentyl,1,1-dimethylethyl(t-butyl), and the like. It may be abbreviated as“Alk”.

As used herein, the term “lower alkoxy” or “lower alkoxy group” means aC₁-C₁₅ linear- or branched-chain saturated aliphatic alkoxy monovalentgroup, which may be unsubstituted or substituted. The group may bepartially or completely substituted with halogen atoms (F, Cl, Br, orI). Non-limiting examples of lower alkoxy groups include methoxy,ethoxy, n-propoxy, 1-methylethoxy(isopropoxy), n-butoxy, n-pentoxy,t-butoxy, and the like.

The term “cycloalkyl” or “cycloalkyl group” means a stable aliphaticsaturated 3- to 15-membered monocyclic or polycyclic monovalent radicalconsisting solely of carbon and hydrogen atoms which may comprise one ormore fused or bridged ring(s), preferably a 3- to 7-membered monocyclicrings. Other exemplary embodiments of cycloalkyl groups include 7- to10-membered bicyclic rings. Unless otherwise specified, the cycloalkylring may be attached at any carbon atom which results in a stablestructure and, if substituted, may be substituted at any suitable carbonatom which results in a stable structure. Exemplary cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl, norbornyl, adamantyl,tetrahydronaphthyl(tetralin), 1-decalinyl, bicyclo[2.2.2]octanyl,1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and thelike.

As used herein, the term “aryl” or “aryl group” means an aromaticcarbocyclic monovalent or divalent radical. In some embodiments, thearyl group has a number of carbon atoms from 5 to 24 and has a singlering (e.g., phenyl or phenylene), multiple condensed rings (e.g.,naphthyl or anthranyl), or multiple bridged rings (e.g., biphenyl).Unless otherwise specified, the aryl ring may be attached at anysuitable carbon atom which results in a stable structure and, ifsubstituted, may be substituted at any suitable carbon atom whichresults in a stable structure. Non-limiting examples of aryl groupsinclude phenyl, naphthyl, anthryl, phenanthryl, indanyl, indenyl,biphenyl, and the like. It may be abbreviated as “Ar”.

The term “heteroaryl” or “heteroaryl group” means a stable aromaticmonocyclic or polycyclic monovalent or divalent radical, which maycomprise one or more fused or bridged ring(s). In some embodiments, theheteroaryl group has 5-24 members, preferably a 5- to 7-memberedmonocyclic or 7- to 10-membered bicyclic radical. The heteroaryl groupcan have from one to four heteroatoms in the ring(s) independentlyselected from nitrogen, oxygen, and sulfur, wherein any sulfurheteroatoms may optionally be oxidized and any nitrogen heteroatom mayoptionally be oxidized or be quaternized. Unless otherwise specified,the heteroaryl ring may be attached at any suitable heteroatom or carbonatom which results in a stable structure and, if substituted, may besubstituted at any suitable heteroatom or carbon atom which results in astable structure. Non-limiting examples of heteroaryls include furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,indolizinyl, azaindolizinyl, indolyl, azaindolyl, diazaindolyl,dihydroindolyl, dihydroazaindoyl, isoindolyl, azaisoindolyl,benzofuranyl, furanopyridinyl, furanopyrimidinyl, furanopyrazinyl,furanopyridazinyl, dihydrobenzofuranyl, dihydrofuranopyridinyl,dihydrofuranopyrimidinyl, benzothienyl, thienopyridinyl,thienopyrimidinyl, thienopyrazinyl, thienopyridazinyl,dihydrobenzothienyl, dihydrothienopyridinyl, dihydrothienopyrimidinyl,indazolyl, azaindazolyl, diazaindazolyl, benzimidazolyl,imidazopyridinyl, benzthiazolyl, thiazolopyridinyl, thiazolopyrimidinyl,benzoxazolyl, benzoxazinyl, benzoxazinonyl, oxazolopyridinyl,oxazolopyrimidinyl, benzisoxazolyl, purinyl chromanyl, azachromanyl,quinolizinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl,isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl,cinnolinyl, azacinnolinyl, phthalazinyl, azaphthalazinyl, quinazolinyl,azaquinazolinyl, quinoxalinyl, azaquinoxalinyl, naphthyridinyl,dihydronaphthyridinyl, tetrahydronaphthyridinyl, pteridinyl, carbazolyl,acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl, and the like.

In general, the present invention provides an improved process forpreparing fluoroquinolones that have Formula I or salts thereof.

wherein R¹ is selected from the group consisting of hydrogen,unsubstituted lower alkyl groups, substituted, lower alkyl groups,cycloalkyl groups, unsubstituted C₅-C₂₄ aryl groups, substituted C₅-C₂₄aryl groups, unsubstituted C₅-C₂₄ heteroaryl groups, substituted C₅-C₂₄heteroaryl groups, and groups that can be hydrolyzed in living bodies;R² is selected from the group consisting of hydrogen, unsubstitutedamino group, and amino groups substituted with one or two lower alkylgroups; R³ is selected from the group consisting of hydrogen,unsubstituted lower alkyl groups, substituted lower alkyl groups,cycloalkyl groups, unsubstituted lower alkoxy groups, substituted loweralkoxy groups, unsubstituted C₅-C₂₄ aryl groups, substituted C₅-C₂₄ arylgroups, unsubstituted C₅-C₂₄ heteroaryl groups, substituted C₅-C₂₄heteroaryl groups, unsubstituted C₅-C₂₄ aryloxy groups, substitutedC₅-C₂₄ aryloxy groups, unsubstituted C₅-C₂₄ heteroaryloxy groups,substituted C₅-C₂₄ heteroaryloxy groups, and groups that can behydrolyzed in living bodies; X is selected from the group consisting ofhalogen atoms; Y is selected from the group consisting of CH₂, O, S, SO,SO₂, and NR⁴, wherein R⁴ is selected from the group consisting ofhydrogen, unsubstituted lower alkyl groups, substituted lower alkylgroups, and cycloalkyl groups; and Z is selected from the groupconsisting of oxygen and two hydrogen atoms.

In one aspect, R¹ is selected from the group consisting of hydrogen,C₁-C₅ (or alternatively, C₁-C₃) substituted and unsubstituted alkylgroups, C₃-C₁₀ (or alternatively, C₃-C₅) cycloalkyl groups, C₅-C₁₄ (oralternatively, C₆-C₁₄, or C₅-C₁₀, or C₆-C₁₀) substituted andunsubstituted aryl groups, C₅-C₁₄ (or alternatively, C₆-C₁₄, or C₅-C₁₀,or C₆-C₁₀) substituted and unsubstituted heteroaryl groups, and groupsthat can be hydrolyzed in living bodies. In one embodiment, R¹ isselected from the group consisting of C₁-C₅ (or alternatively, C₁-C₃)substituted and unsubstituted alkyl groups.

In another aspect, R² is selected from the group consisting ofunsubstituted amino group and amino groups substituted with one or twoC₁-C₅ (or alternatively, C₁-C₃) alkyl groups.

In still another aspect, R³ is selected from the group consisting ofhydrogen, C₁-C₅ (or alternatively, C₁-C₃) substituted and unsubstitutedalkyl groups, C₃-C₁₀ (or alternatively, C₃-C₅) cycloalkyl groups, C₁-C₅(or alternatively, C₁-C₃) substituted and unsubstituted alkoxy groups,C₅-C₁₄ (or alternatively, C₆-C₁₄, or C₅-C₁₀, or C₆-C₁₀) substituted andunsubstituted aryl groups, C₅-C₁₄ (or alternatively, C₆-C₁₄, or C₅-C₁₀,or C₆-C₁₀) substituted and unsubstituted heteroaryl groups, and C₅-C₁₄(or alternatively, C₆-C₁₄, or C₅-C₁₀, or C₆-C₁₀) substituted andunsubstituted aryloxy groups. In one embodiment, R³ is selected from thegroup consisting of C₃-C₁₀ (or alternatively, C₃-C₅) cycloalkyl groups.

In yet another aspect, X is selected from the group consisting of Cl, F,and Br. In one embodiment, X is Cl. In another embodiment, X is F.

In a further aspect, Y is hydrogen. In still another aspect, Z comprisestwo hydrogen atoms.

In one embodiment, the fluoroquinolone carboxylic acid has a Formula Ia.

In one aspect, the present invention provides an improved process ofpreparing fluoroquinolones having Formula I. The process comprisescontacting a first compound having Formula II with a second compoundhaving Formula III to produce a fluoroquinolone having Formula I,wherein the first compound and the second compound are represented by

wherein R¹, R², R³, X, Y, and Z have the meanings as disclosed above.

In another aspect, the first compound having Formula II, which is usedin a process of the present invention as disclosed above, can beprepared according a procedure disclosed in published European PatentApplication EP 0230946 A2, which is incorporated in its entirety byreference. For example, the first compound having Formula II is preparedby a process comprising: (a) reacting a compound having Formula X withan equimolar or excess amount of orthoformic acid ester in aceticanhydride (1 to 20-fold volume per total volume of the other reagents)at a temperature in the range from about room temperature to about 200°C. (preferably, from about 100° C. to about 150° C.) for a time fromabout 30 minutes to 24 hours to produce a compound having Formula XI;(b) treating the compound having Formula XI with an equimolar or excessamount of an amine having a formula of NH₂R³ in a solvent comprising analcohol (preferably, ethanol or propanol), to convert the compoundhaving Formula XI to a compound having Formula XII; (c) treating thecompound having Formula XII with a fluoride salt (such as one selectedfrom the group consisting of sodium fluoride, potassium fluoride, andlithium fluoride) in a solvent selected from the group consisting ofdioxane, dimethylformamide, dimethylsulfoxide, and sulfolane atemperature in the range from about 0° C. to about 200° C. (preferably,from about 50° C. to about 150° C.) for a time in the range from about30 minutes to about 24 hours, to produce the compound having Formula II.The compounds having Formulae X, XI and XII are shown below.

wherein R⁷ is unsubstituted lower alkyl groups, substituted lower alkylgroups, unsubstituted C₅-C₂₄ aryl groups (or alternatively, C₅-C₁₄, orC₅-C₁₀, or C₆-C₁₀), cycloalkyl groups, substituted C₅-C₂₄ and groups (oralternatively, C₅-C₁₄, or C₅-C₁₀, or C₆-C₁₀), unsubstituted C₅-C₂₄heteroaryl groups (or alternatively, C₅-C₁₄, or C₅-C₁₀, or C₆-C₁₀), andsubstituted C₅-C₂₄ heteroaryl groups (or alternatively, C₅-C₁₄, orC₅-C₁₀, or C₆-C₁₀); and

In another aspect, the second compound having Formula III can beprepared by cyclization of various amino acids. For examples, suchcompounds having Formula III can be prepared according to the methodsdisclosed in D. W. Adamson, J. Chem. Soc., p. 39 (1943); R. Pellegata etal., Synthesis, p. 614 (1978); and M. Saburi et al., Bull. Chem. Soc.Japan, Vol. 60, pp 141-48 (1987). These references are incorporatedherein by reference. Alternatively, various azepines having generalFormula III can be prepared according to the methods disclosed in H.Chong et al., J. Chem. Soc. Perkin Trans., Vol. 1, 2080-86 (2002); J.Barluenga, Pure Appl. Chem., Vol. 74, No. 8, 1317-25 (2002); and T.Naito et al. (available athttp://www.ch.ic.ac.uk/etoc/echet96/papers/054/index.htm. ElectronicConference on Heterocyclic Chemistry, Jun. 24 to Jul. 22, 1996, visitedon Dec. 22, 2006), using appropriate starting materials. The referencesby H. Chong et al., and by J. Barluenga are incorporated herein byreference.

In one embodiment of the present invention, a fluoroquinolone havingFormula I is prepared as follows. One mole of the compound havingFormula II is reacted with about 1-5 moles of the compound havingFormula III in a solvent such as acetonitrile, dimethylsulfoxide, or thelike, at a temperature in the range from about room temperature to about100° C. for a time in the range from about 10 minutes to about 7 days.After the reaction, the precipitate is collected by filtration andwashed, for example at room temperature, with a sufficient quantity of asuitable solvent, such as methanol, chloroform, ether, or the like, toobtain a crude product. The crude product is purified, for example, bysilica gel column chromatography or by recrystallization to obtain thefluoroquinolone having Formula I.

In another embodiment of the present invention, a fluoroquinolone havingformula IV is prepared as follows. One mole of the compound havingFormula II is reacted with about 1-5 moles of the compound havingFormula V in a solvent such as acetonitrile, dimethylsulfoxide, or thelike, at a temperature in the range from about room temperature to about100° C. for a time in the range from about 10 minutes to about 7 days toproduce a compound having Formula VI. An amount of an acid or base(depending on whether the cleavage of the protecting group is acid- orbase-catalyzable), such as from about 0.1 to about 5 moles per mole ofthe compound having Formula V, is added to the reaction mixture to allowfor the splitting of the protecting group R⁶ from the protected amino—NR⁵ group. In one embodiment, after this reaction, a base is added tothe reaction mixture to convert free HF and HX acids to their salts(resulting pH is about 7), which are washed, for example at roomtemperature, from the mixture to produce a crude product. The crudeproduct is purified, for example, by silica gel column chromatography orby recrystallization to obtain the fluoroquinolone having Formula IV.

In one embodiment, the compound having general Formula V has particularFormula VII.

This compound can be prepared by the following reaction.

The nitrophenylalkylidene protecting group is disclosed in the abovescheme only for illustrative purposes. Other protecting groups can beused in place of the nitrophenylalkylidene group, as can be recognizedby people having skill in the art of organic synthesis. For example,another commonly used protecting group for the amine moiety is thet-butoxycarbonyl (“t-Boc”), which may be finally cleaved by an anhydrousacid catalyst, such as HCl to yield the amino group. Still anotherexample of a protecting group for the amine moiety is thefluorenylmethoxycarbonyl (“Fmoc”), which can be cleaved by an anhydrousbase catalyst, such as ammonia, piperidine, or morpholine.

In still another aspect, a process for preparing a fluoroquinolonecarboxylic acid having Formula Ia comprises: (a) contacting a compoundhaving Formula IIa with a compound having Formula VIIa at a temperaturein the range from about room temperature to about 100° C. for a timefrom about 10 minutes to about 7 days, to produce a compound havingFormula VIa

(b) contacting the compound having Formula VIa with an amount of HClequal to about 0.1 to about 5 moles per mole of the compound havingFormula VIIa at a temperature in the range from about room temperatureto about 100° C., in a presence of methanol, to produce thefluoroquinolone carboxylic acid having Formula Ia; and (c) recoveringthe fluoroquinolone carboxylic acid having Formula Ia.

In yet another aspect, the crude product can comprise a mixture ofenantiomers of the compound having Formula I or enantiomers of thecompound having Formula IV, as tire case may be. One of the enantiomersis often more soluble in water than the other. Therefore, another aspectof the present invention comprises the separation of one of theenantiomers of a crude product by washing or dissolving the crudeproduct with water, and recovering such an enantiomer from the aqueousphase.

Therefore, in another aspect of the present invention, a process ofpreparing an enantiomer of a fluoroquinolone having Formula I comprises:(a) contacting a first compound having Formula II with a second compoundhaving Formula III to produce a crude enantiomeric mixture comprisingenantiomers of the fluoroquinolone having Formula I; (b) recovering thecrude enantiomeric mixture; (c) contacting the crude enantiomericmixture thus recovered with water to produce an aqueous solution; and(d) recover the enantiomer of the fluoroquinolone having Formula I fromthe aqueous solution. In one embodiment, the step of contacting thecrude enantiomeric mixture with water is carried out at a temperature ina range from about room temperature to about 80° C., or from about roomtemperature to about 50° C. In another embodiment, the step ofcontacting the crude enantiomeric mixture with water is carried out atabout room temperature.

In still another aspect, a process of preparing an enantiomer of afluoroquinolone having Formula IV comprises; (a) contacting a firstcompound having Formula II with a third compound having Formula V toproduce a fourth compound having Formula VI; (b) contacting the fourthcompound with a catalyst capable of assisting a cleavage of a protectinggroup from the R⁵ group, to produce a crude enantiomeric mixture offluoroquinolones having Formula IV; (c) recovering the crudeenantiomeric mixture; (c) contacting the crude enantiomeric mixture thusrecovered with water to produce an aqueous solution; and (d) recover theenantiomer of the fluoroquinolone having Formula IV from the aqueoussolution; wherein X has the meaning disclosed above. In one embodiment,the step of contacting the crude enantiomeric mixture with water iscarried out at a temperature in a range from about room temperature toabout 80° C., or from about room temperature to about 50° C. In anotherembodiment, the step of contacting the crude enantiomeric mixture withwater is carried out at about room temperature.

In a further aspect the present invention provides a process forpreparing fluoroquinolones having Formula I. The process comprises: (a)contacting a compound having Formula XIII with a compound having FormulaIII to produce a compound having Formula XIV; and (b) halogenating thecompound having Formula XIV with a halogenating agent to produce thefluoroquinolones having Formula I; wherein R¹ is selected from the groupconsisting of hydrogen, unsubstituted lower alkyl groups, substitutedlower alkyl groups, cycloalkyl groups, unsubstituted C₅-C₂₄ and groups,substituted C₅-C₂₄ aryl groups, unsubstituted C₅-C₂₄ heteroaryl groups,substituted C₅-C₂₄ heteroaryl groups, and groups that can be hydrolyzedin living bodies; R² is selected from the group consisting of hydrogen,unsubstituted amino group, and amino groups substituted with one or twolower alkyl groups; R³ is selected from the group consisting ofhydrogen, unsubstituted lower alkyl groups, substituted lower alkylgroups, cycloalkyl groups, unsubstituted lower alkoxy groups,substituted lower alkoxy groups, unsubstituted C₅-C₂₄ aryl groups,substituted C₅-C₂₄ aryl groups, unsubstituted C₅-C₂₄ heteroaryl groups,substituted C₅-C₂₄ heteroaryl groups, unsubstituted C₅-C₂₄ aryloxygroups, substituted C₅-C₂₄ aryloxy groups, unsubstituted C₅-C₂₄heteroaryloxy groups, substituted C₅-C₂₄ heteroaryloxy groups, andgroups that can be hydrolyzed in living bodies; X is selected from thegroup consisting of halogen atoms; Y is selected from the groupconsisting of CH₂, O, S, SO, SO₂, and NR⁴, wherein R⁴ is selected fromthe group consisting of hydrogen, unsubstituted lower alkyl groups,substituted lower alkyl groups, and cycloalkyl groups; and Z is selectedfrom the group consisting of oxygen and two hydrogen atoms. Thecompounds having Formulae XIII, III, and XIV are shown below.

In one embodiment, a process for preparing a fluoroquinolone carboxylicacid having Formula Ia comprises: (a) contacting a compound havingFormula XV with a compound having Formula VIIa at a temperature in therange from about room temperature to about 100° C. for a time from about10 minutes to about 7 days, to produce a compound having Formula XVI;(b) chlorinating the compound having Formula XVI with a chlorinatingagent to produce the fluoroquinolones having Formula XVII; (c)contacting the compound having Formula XVII with an amount of HCl equalto about 0.1 to about 5 moles per mole of the compound having FormulaVIIa at a temperature in the range from about room temperature to about100° C. in a presence of methanol, to produce the fluoroquinolonecarboxylic acid having Formula Ia; and (d) recovering thefluoroquinolone carboxylic acid having Formula Ia. The compounds havingFormulae XV, VIIa, XVI, and XVII are shown below.

In one embodiment, the chlorinating agent is selected from the groupconsisting of sulfuryl chloride, chlorine, N-chlorosuccinic acid imide,and the like, in a suitable solvent, such as chloroform,dichloromethane, acetic acid, methanol, ethanol, and the like. The stepof chlorinating can be carried out at a temperature in the range fromabout 0 to about 100° C. (when the step of chlorinating is carried outin a liquid medium, it may be preferred to employ a temperature lowerthan the boiling point of the solvent) for about 10 minutes to about 48hours.

In yet another aspect, the present invention provides a fluoroquinolonehaving Formula I, Ia, or IV prepared by any appropriate processdisclosed herein.

In some embodiments, a process of the present invention has advantagesover the process disclosed in U.S. Pat. Nos. 5,385,900 and 5,447,926 inthat such a process is simpler and does not require the last step ofU.S. Pat. Nos. 5,385,900 and 5,447,926 for the attachment of a halogenatom to the position 8 on the compounds having Formulae I, Ia, and IV.This step requires the use of an excess amount of a halogenating agentsuch as sulfuryl chloride, chlorine, bromine, iodine, fluorine,N-chlorosuccinic acid imide, N-bromosuccinic acid imide, or the like.The use of such halogenating agents, especially in the gas phase,requires installation of precautionary measures in the manufacturingprocess, which would increase the complexity and cost of themanufacture.

Alternatively, in some other embodiment, a process of the presentinvention has advantages over the process disclosed in U.S. Pat. Nos.5,385,900 and 5,447,926 because a process of the present inventioneffects a reaction on the material having Formula XIII, which is morereadily available and more economically favorably than another material,identified as Compound 2 in these patents.

Compounds of this family of fluoroquinolones can be used effectivelyagainst the survival of microbial pathogens. For example, the compoundshaving Formula I, Ia, or IV are potent antimicrobial agents and arefound to be effective against the survival of Gram-positive bacteria,such as Bacillus subtilus, Staphylococcus aureus, Staphylococcusepidermis, Sarcina lutea, Streptococcus faecalis, and Micrococcuslysodeikticus; Grain-negative bacteria, such as Escherichia coli,Samonella typhi, Shigella flexneri, Pseudomonas aeruginosa, Kleisielapneumonias, Proteus vulgaris, Proteus rettgeri, and Serratiamarcesscens; and a metricillin-resistant strain of Streptococcus aureus.See; e.g., U.S. Pat. Nos. 5,385,900 and 5,447,926; which areincorporated herein by reference in their entirety.

A fluoroquinolone compound prepared by any method disclosed herein canbe formulated into an antimicrobial composition for topical, oral,systemic, ocular, or intraocular administration. Such a compositioncomprises a fluoroquinolone compound and an excipient appropriate forthe administration, as can be determined by a person having skill in theart of pharmaceutical formulation for the applications disclosed above.For example, various excipients known in the art can be used toformulate a solution, suspension, dispersion, ointment, gel, capsule, ortablet. A fluoroquinolone compound prepared by any method disclosedherein is particularly suitable for a treatment, reduction,amelioration, or prevention of infections of the eye, ear, nose, throat,or respiratory system caused by bacteria, including, but not beinglimited to, those bacteria disclosed above. In one embodiment, such afluoroquinolone is formulated into an ophthalmic solution, ointment,suspension, dispersion, or gel.

While specific embodiments of the present invention have been describedin the foregoing, it will be appreciated by those skilled in the artthat many equivalents, modifications, substitutions, and variations maybe made thereto without departing from the spirit and scope of theinvention as defined in the appended claims.

1. A process of preparing a fluoroquinolone enantiomer having Formula IVor salts thereof, the method comprising: (a) contacting a first compoundhaving Formula II with a third compound having Formula V to produce afourth compound having Formula VI, wherein the fluoroquinolone havingFormula IV, the first compound, the third compound, and the fourthcompound are represented by

 wherein R¹ is selected from the group consisting of hydrogen,unsubstituted lower alkyl groups, substituted lower alkyl groups,cycloalkyl groups, unsubstituted C₅-C₂₄ aryl groups, substituted C₅-C₂₄aryl groups, unsubstituted C₅-C₂₄ heteroaryl groups, substituted C₅-C₂₄heteroaryl groups, and groups that can be hydrolyzed in living bodies;R³ is selected from the group consisting of hydrogen, unsubstitutedlower alkyl groups, substituted lower alkyl groups, cycloalkyl groups,unsubstituted lower alkoxy groups, substituted lower alkoxy groups,unsubstituted C₅-C₂₄ aryl groups, substituted C₅-C₂₄ aryl groups,unsubstituted C₅-C₂₄ heteroaryl groups, substituted C₅-C₂₄ heteroarylgroups, unsubstituted C₅-C₂₄ aryloxy groups, substituted C₅-C₂₄ aryloxygroups, unsubstituted C₅-C₂₄ heteroaryloxy groups, substituted C₅-C₂₄heteroaryloxy groups, and groups that can be hydrolyzed in livingbodies; X is selected from the group consisting of halogen atoms; Y isCH₂; Z is selected from the group consisting of oxygen and two hydrogenatoms; and R⁵ comprises a protected amino group having a formula or—NR⁶, wherein R⁶ comprises a protecting group that is capable of leavingthe protected amino group —NR⁶; and (b) contacting the fourth compoundwith a sufficient amount of a catalyst and at a condition sufficient toeffect a cleavage of the protecting group R⁶ from the —NR⁶ group, toproduce a fluoroquinolone having Formula IV; wherein the orientation ofR₂ is preserved throughout the process.
 2. The process of claim 1,wherein R¹ is selected from the group consisting of hydrogen, C₁-C₅substituted and unsubstituted alkyl groups, C₃-C₁₀ cycloalkyl groups,C₆-C₁₄ substituted and unsubstituted aryl groups, C₆-C₁₄ substituted andunsubstituted heteroaryl groups, and groups that can be hydrolyzed inliving bodies; R³ is selected from the group consisting of hydrogen,C₁-C₅ substituted and unsubstituted alkyl groups, C₃-C₁₀ cycloalkylgroups, C₁-C₅ substituted and unsubstituted alkoxy groups, C₅-C₁₄substituted and unsubstituted aryl groups, C₅-C₁₄ substituted andunsubstituted heteroaryl groups, and C₅-C₁₄ substituted andunsubstituted aryloxy groups; R⁶ is selected from the group consistingof nitrophenylalkylidene, t-Boc, and Fmoc; and X is selected from thegroup consisting of Cl, F, and Br.
 3. The process of claim 1, wherein R¹is selected from the group consisting of hydrogen, C₁-C₅ substituted andunsubstituted alkyl groups and groups that can be hydrolyzed in livingbodies; R³ is selected from the group consisting of C₃-C₁₀ cycloalkylgroups; R⁶ comprises a nitrophenylalkylidene group; X is selected fromthe group consisting of Cl and F; Y comprises CH₂; and Z comprises twohydrogen atoms.
 4. The process of claim 1, wherein the catalyst isselected from the group consisting of acids and bases.
 5. The process ofclaim 3, wherein the step of contacting is carried out at a temperaturein a range from about room temperature to about 100° C.
 6. The processof claim 3, wherein the catalyst is hydrochloric acid.
 7. The process ofclaim 1, wherein the process further comprises recovering the enantiomeris carried out by recrystallization.
 8. A process for preparing afluoroquinolone carboxylic acid enantiomer having Formula Ia or saltsthereof, the process comprising: (a) contacting a compound havingFormula IIa with a compound having Formula VIIa at a temperature in therange from about room temperature to about 100° C. for a time from about10 minutes to about 7 days, to produce a compound having Formula VIa,wherein the fluoroquinolone having Formula Ia and the compounds havingFormulae IIa, VIa, and VIIa are represent by

(b) contacting the compound having Formula VIa with an amount of HClequal to about 0.1 to about 5 moles per mole of the compound havingFormula VIIa at a temperature in the range from about room temperatureto about 100° C., in a presence of methanol to produce thefluoroquinolone carboxylic acid having Formula Ia; and (c) recoveringthe fluoroquinolone carboxylic acid enantiomer having Formula Ia;wherein the orientation of the amino group is presented throughout theprocess.
 9. The process of claim 8, wherein the step of recovering thefluoroquinolone carboxylic acid enantiomer is carried out byrecrystallization.